P875: REPLACING STEROIDS IN TRANSPLANT-INELIGIBLE MULTIPLE MYELOMA: THE PHASE 2 ISATUXIMAB-BORTEZOMIB-LENALIDOMIDE-DEXAMETHASONE REST STUDY
Authors: Frida Bugge Askeland, Einar Haukås, Tobias S. Slørdahl, Anja Klostergaard, Tatjana Alexandersen, Diana Schjøll, Anna Lysén, Emil Hermansen, Fredrik Schjesvold
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Standard therapies for newly diagnosed multiple myeloma (NDMM) patients who are ineligible for autologous stem-cell transplantation (ASCT) have been lenalidomide-dexamethasone (Rd), bortezomib-lenalidomide-dexamethasone (VRd) or bortezomib-melphalan-prednisone (VMP). The benefit of adding an anti-CD 38 monoclonal antibody (mAb) to the standard treatments of VMP and Rd has been demonstrated in two large phase 3 studies (Facon, 2019. Mateos, 2018). Isatuximab is an anti-CD38 mAb approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone to treat relapsed/refractory MM, and has also shown clinical responses as combination therapy to treat NDMM (Trudel, 2019). Corticosteroids have been the backbone of most myeloma-targeted therapies since the discovery of their effectiveness. Due to the continuous treatment paradigm, the cumulative dose of corticosteroids in patients is substantial. Steroids inflict reduction in both short- and long-term quality of life and increase patients’ receptiveness for infections. Infections are one of the main reasons for complications and death during active first line treatment and the rate rises with age (Mothy, 2019). Both steroid-free regimens and regimens with reduced corticosteroids have demonstrated improved safety and similar efficacy as regimens containing steroids (O´Donnell, 2018. Rajkumar, 2010. Richardson, 2005). Aims: The study evaluates isatuximab (Isa) in combination with bortezomib (V) and lenalidomide (R) with minimal dexamethasone (d) as first-line treatment in transplant-ineligible patients. The primary endpoint is the number of patients who achieve measurable residual disease negative (Euroflow NGF 10-5) complete response during and/or after 18 cycles of study treatment. Secondary endpoints include progression free survival, overall survival, overall response rate, safety evaluations and patient-reported outcome. Methods: The REST study is an academic, single arm, open-label, phase 2 study (ClinicalTrial.gov; NCT04939844) of NDMM patients ineligible for ASCT. The patients receive Isa-VRd (Isa:10 mg/kg IV Days 1, 8, 15, 22 during cycle 1, QW cycle 2-18; V: 1,3 mg/m2 SC Days 1,8,15 during cycle 1-8; R: 25 mg PO Days 1-21 during all cycles; d: 20 mg PO Days 1,8,15,22 only for the first 2 cycles), all 28-day cycles. Results: As of January 31, 2023, recruitment is completed with 51 patients enrolled. Baseline characteristics can be found in Table 1. At data-cutoff, the median number of cycles started by patients was 9 (range 1-21) and the median duration of exposure was 34 (range 1-76) weeks. 46 patients were still on study, 1 patient died of staphylococcus aureus septicemia, 3 patients discontinued due to disease progression and 1 patient for poor compliance (after 1 cycle). 23 patients developed 43 grade ≥3 non-hematological adverse events (AE), including infections (n=16), vasovagal syncope (n=5), bone pain (n=3), acute renal failure (n=3), diarrhea (n=3), increased transaminases (n=3) peripheral neuropathy (n=2), maculopapular rash (n=1), venous thromboembolism (n=1), reduced general condition (n=1), opiate intoxication (n=1), arthritis (n=1) and gastrointestinal hemorrhage (n=1). 2 patients have discontinued study treatment before cycle 19 due to drug toxicity or adverse events (all grade 2 or lower). At a median follow up of 8 months, 39 patients was evaluated for response. The ORR was 97% (38/39 patients) and the ≥very good partial response rate was 66.6% (26/39 patients). Summary/Conclusion: Isa-VRd in the transplant ineligible population has a tolerable safety profile and is showing encouraging preliminary efficacy in NDMM ineligible for transplant. Follow-up is ongoing. Table 1:Acknowledgements: Sanofi sponsors the REST study. Keywords: Monoclonal antibody, Minimal residual disease (MRD), Multiple myeloma